Critical Illness and Changes in Sensory Perception

Proceedings of the Nutrition Society (2007), 66, 331–345 DOI:10.1017/S0029665107005599 g The Author 2007

Critical illness and changes in sensory perception

Susan S. Schiffman Department of Psychiatry, 54212 Woodhall Building, Duke University Medical Center, Durham, NC 27710–3259, USA

Impairments of sensory perception that occur during a period of critical care can seriously impact on health and nutritional status, activities of daily living, independence, quality of life and the possibility of recovery. It is emphasized from the outset that sensory losses in critically- ill patients may or may not be related to their current medical condition. The present paper provides an overview of all ﬁve senses (vision, hearing, taste, smell and touch) and describes the factors that contribute to sensory losses in critically-ill patients, including medications, medical conditions and treatments and the process of aging itself. Cancer and stroke are two critical illnesses in which profound sensory decrements often occur. Many sensory complaints in patients with cancer are related to alteration in sensory signals caused by damage to the sensory receptors. However, some complaints, such as taste aversions in patients with cancer, are not related to altered sensory physiology per se but to learned aversions that arise during the noxious effects of radiotherapy and chemotherapy. The paper also reviews a study in which the sensory performance (of all ﬁve senses) was compared in three groups of elderly subjects: (1) patients who had undergone coronary artery bypass surgery; (2) patients with cardiovascular conditions but with no history of surgery; (3) healthy non-medicated age-matched controls. Performance of patients who had undergone coronary artery bypass surgery was worse than that for the other two groups, with taste and smell losses greater than for the other senses. The study demonstrates that critical illness (e.g. coronary artery bypass surgery) can exacerbate sensory losses in an older cohort.

Senses: Aging: Critical illness: Medical conditions: Medications

Advancements in the treatment of critical illnesses such as weight loss and ultimately increased risk of morbidity and cancer, heart attack and stroke have dramatically length- mortality (Toth & Poehlman, 2000). Thus, awareness of ened life expectancy for patients who survive with these potential sensory impairments in the critically-ill patient by conditions. While medical science has substantially im- physicians and other health providers is crucial for making proved the prognosis for individuals who suffer from many decisions about appropriate treatments that optimize med- critical illnesses, there are often negative physiological and ical (including nutritional) care. perceptual effects that accompany prolonged survival that The elderly are more likely than younger cohorts to can have a serious impact on daily functioning and quality suffer from critical illnesses, including strokes (Di Carlo of life. For example, patient complaints of sensory alter- et al. 2006), heart attacks (Hellermann et al. 2002; Yawn ations in vision, hearing, taste, smell and touch often occur et al. 2004) and cancer (Cohen, 1998), and are also more during a period of critical care and persist with continued likely to suffer from sensory losses (Schiffman & Zervakis, survival. These sensory changes can be qualitative, quan- 2002; Schiffman et al. 2003). For this reason, the present titative and/or affective. As experience of the world review article will provide an overview of changes in sen- depends largely on the senses, losses in sensory perception sory perception that can occur in patients with critical ill- can seriously affect overall health, nutritional status, nesses, with a special focus on the elderly who as a group activities of daily living and quality of life. Sensory im- suffer disproportionately from sensory loss. Understanding pairments that reduce the ability to procure and appreciate the sensory impairments of an older cohort is important food can lead to inadequate energy and nutrient intake, because man-life expectancy is increasing dramatically,

Abbreviations: AMD, age-related macular degeneration; NST, nucleus of the solitary tract; ORN, olfactory receptor neurons. Corresponding author: Professor Susan S. Schiffman, email [email protected] and [email protected]

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with the number of elderly expected to reach 1.21 billion Sekuler, 2000; Schiffman et al. 2003). At approximately worldwide in 2025 (US Senate Special Committee on 65 years of age performance is diminished on tests of far Aging, 1985–6). Many older patients are not consciously visual acuity (resolution of spatial detail) and contrast aware of age-related sensory changes that take place sensitivity. Contrast sensitivity is the ability to recognize slowly over time; however, perceptual changes often reach subtle differences in shading and colour between an object consciousness if they are exacerbated during a critical ill- and its background. Evaluation of contrast sensitivity is ness. considered a more sensitive measure for detecting losses in It should be emphasized from the outset that sensory visual acuity than the standard graded symbols of the losses in critically-ill patients may or may not be related to Snellen eye chart. A typical method for testing contrast their current medical condition. For this reason, the present sensitivity is the use of gratings with alternating light and article will first describe typical sensory losses that occur dark bars (or stripes) from low frequencies (wider bars) to with advancing age as well as how disease states, including high frequencies (thin bars). Age-related losses are first critical illnesses, impact on sensory perception. The effect seen at high spatial frequencies and low contrast. of medications on the senses will also be addressed be- Losses in peripheral vision also occur, with the visual cause use of medication is elevated in older individuals, field reduced to two-thirds by age 75 years and to half by especially during a period of critical care (Schiffman, age 90 years. The visual field is the entire area (both hori- 1997; Noble, 2003; Schiffman et al. 2003), and because zontal and vertical) that is seen while gazing straight adverse drug reactions are observed two to three times ahead. The consequence of reduction of the size of the more frequently in geriatric patients compared with field is that the elderly do not recognize movement or ob- younger adults (Turnheim, 1998, 2004). Finally, the results jects at the periphery of the field. Loss of warning signals of a research study are described that provide the first from peripheral vision makes the elderly more vulnerable quantitative data on the amount of sensory loss for all five to hazards while driving or walking. As the peripheral senses that can be expected with one type of critical con- receptors are rods, these losses are especially severe in dim dition, i.e. coronary artery bypass surgery. light. The loss in peripheral vision is a result in part of decreased pupil size (miosis) and in part of reduced sensitivity of the rods. The peripheral field can be screened Vision simply by occluding one eye and determining when the patient can see an object (e.g. index finger) as it moves Changes in the visual system with age from outside the unoccluded lateral field into the visual Many adverse physiological changes in the structure and field. Aging is also associated with changes in adaptation function of the eye can occur during the aging process to light such that the older retina requires more time to (Weale, 2000; Schiffman et al. 2003). Lacrimation (tear adapt from light to dark and to adjust to bright light. flow) decreases substantially over the lifespan causing ‘dry Impairments in the rate and maximum level of dark adapt- eye’ in many older individuals. As lacrimal fluids provide ation can have profound effects on activities such as a smooth corneal surface for refraction, decreased tear driving at night, reading a menu in a restaurant or reading a production can reduce the clarity of an image. The pupil programme in a theatre. decreases in size with age (called ‘senile miosis’) so that the elderly need brighter illumination to see. There is re- Age-related eye diseases duced transparency of the lens with attenuation of light, particularly short wavelengths including blue and violet. Progression of degenerative changes beyond those of nor- The accommodative power of the lens decreases with age mal aging leads to a variety of age-related ocular diseases, (presbyopia) so that most elderly require reading glasses. including cataracts, macular degeneration and glaucoma Alterations in both the aqueous humour and the vitreous (Weale, 2000). Diabetic retinopathy also increases in pre- humour also occur. The aqueous humour is the clear valence with progression of the disease. Cataracts (because watery fluid that circulates in the chamber of the eye be- of excessive lens opacity) impair vision because a cloudy tween the cornea and the lens. With increasing age the lens does not transmit a sharply-focused image to the drainage network for the aqueous humour can become retina. Blurred vision and sensitivity to glare are common partially blocked, which leads to increased intraocular eye complaints of individuals with cataracts. Risk factors for pressure and potential damage to vision. The gelatinous the development of cataracts include age, trauma to the vitreous humour that fills the eyeball between the retina eye, sun exposure, malnutrition, use of steroids and smok- and the lens tends to liquefy, contract and separate from ing. The impaired vision from cataracts can be reversed by the retina. This process creates ‘floaters’ in front of the surgical removal of the clouded lens and replacement with retina that can be very distressing for observant indivi- a clear plastic intraocular lens. Age-related macular duals. Age-related alterations in the structure of protein degeneration (AMD) is the gradual and irreversible loss of molecules in the cornea, lens and vitreous humour generate vision caused by degeneration of the macula, a small cir- complaints of glare. Retinal changes also occur with ad- cular membrane at the centre of the retina that includes vancing age, including a reduction in the number of nerve the fovea, which is responsible for visual acuity (detail cells within the retina along with alterations in the retinal vision), daytime (photopic) vision and colour vision (the vasculature. macula is a cone-enriched area of the retina). AMD Perceptual visual losses accompany age-related ocular impairs central vision that is required for reading, driving changes in the absence of disease (Faye, 2000; Sekuler & and other activities that involve fine detail and visual

contrast. Individuals with AMD report that objects dis- clinically for cancer prevention, causes alterations in dark appear perceptually behind a blind spot, that faces are adaptation (Baglietto et al. 2000). The probable cause is difficult to recognize and that straight lines appear wavy. that fenretinide lowers circulating retinol and thus affects In the worst cases there is a complete loss of central vision; night vision. Cisplatin, which is used in the treatment of however, total blindness does not occur because peripheral solid tumours, has been associated with sudden onset of vision is unaffected. Heredity, smoking, obesity, CVD, blindness. This severe visual loss appears to be a mani- exposure to sunlight, high blood pressure, high cholesterol, festation of Mg deficiency because the visual symptoms ethnicity, diabetes and oxidation of the macula as a result are reversed with correction of the electrolyte abnormality of inadequate intake of antioxidants can play a role in the (Al-Tweigeri et al. 1999). Visual functioning can be pro- development of AMD. AMD is the most common cause of foundly impaired after a posterior cerebral artery stroke blindness in individuals >50 years of age. There are two (Schoenfeld et al. 2002). Stroke often exacerbates age- forms of AMD, wet and dry. Wet AMD occurs with the related loss of peripheral vision associated with decreased growth (as well as haemorrhage) of abnormal blood vessels pupil size (miosis) and reduced sensitivity of the rods. behind the retina. Dry AMD involves the breakdown of the Visual memory, including total time to complete a test as light-sensitive cells in the macula but no leakage of fluid. well as the number of correct answers, can also be im- A common early sign of dry AMD is drusen, i.e. yellow paired in patients who have had a stroke (Yaretzky et al. deposits in the retina that can be detected during a com- 1995). Anterior ischaemic optic neuropathy with sub- prehensive dilated-eye examination even before there is sequent visual loss occurs in some patients who have vision loss. The central visual field is screened with an undergone cardiac surgery with cardiopulmonary bypass Amsler grid (a checkerboard of horizontal and vertical (Tidow-Kebritchi & Jay, 2003). Cortical blindness and lines). The straight lines of the grid appear wavy to an visual disorientation occurs in some patients who have individual with AMD. sustained bilateral occipital and parietal lobe ischaemia Glaucoma results from damage to the optic disc and during coronary artery bypass surgery (Russell & Bhar- optic nerve in the eye that typically occurs from a rise in ucha, 1978). Altered visual functioning that is associated intraocular pressure. This increase in pressure is caused by with vascular hypertension in the absence of eye disease an imbalance in fluid production and drainage of the aqu- (Eisner & Samples, 2003) can be exacerbated by cardiac eous humour as a result of partial blockage in the trabe- surgery. Infections and malnutrition are also well known to cular meshwork (situated in the angle where the iris and impact on visual functioning (Oduntan, 2005). Interest- cornea meet). The most common type of glaucoma is ingly, visual functioning has been reported to be impaired open-angle glaucoma, which develops slowly with gradual in patients undergoing long-term total parenteral nutrition and painless loss of sight. Gradual loss of outer (peri- (Vinton et al. 1990). pheral) vision occurs first, with central vision being the last to be affected because the optic nerve fibres mediating Medications that affect visual functioning peripheral vision are the first to be compressed and damaged; i.e. loss of visual function in glaucoma is the There are a vast number of medications that induce visual opposite of that found in AMD. The peripheral visual field side effects (Fraunfelder & Fraunfelder, 2001; Physicians’ loss in end-stage glaucoma is analogous to looking down Desk Reference, 2005). Blurred vision is a common side the barrel of a gun. Overall, the prevalence of open-angle effect of hundreds of medications, including antihistamines glaucoma increases exponentially from <1% during the and antihypertensive drugs. There are multiple causes of fifth decade of life to 10% in the ninth decade, with some blurred vision, including anticholinergic properties that variation depending on ethnicity. Sudden increases in impair accommodation. Conversely, other drugs alter intraocular pressure can also occur (acute closed-angle vision by constricting the pupil, such as miotic eye drops glaucoma) with immediate symptoms of blurred vision, for glaucoma (e.g. pilocarpine and carbachol); heroin halos around lights, reddening of the eye and severe eye usage is also associated with constricted pupils. Drugs can pain, which lead to permanent vision loss. Aging, genetics, also directly damage the eye, e.g. retinal toxicity from myopia, diabetes, hypertension, previous eye surgery and antimalarial drugs and cataract formation from steroids. steroid use have all been implicated as risk factors in the Bisphosphonates (such as alendronate, clodronate, eti- development or exacerbation of glaucoma. dronate, ibandronate, pamidronate, risedronate and zolen- dronate), which are used to treat osteoporosis as well as hypercalcaemia of malignancy, osteolytic bone metastases Critical illnesses that affect the eye of both breast cancer and multiple myeloma and Paget’s Visual disturbances have been reported in many critical disease of the bone, as well as other indications depending medical conditions, including cancer, stroke, cardio- on the product, are associated with adverse changes in vascular surgery and infectious diseases. These visual visual perception (Canadian Family Physician, 2004). losses can be caused or exacerbated by the medical con- These alterations include blurred or double vision, de- dition itself or by its treatment. Chemotherapy for a broad creased vision and ‘floaters’, as well as eye pain and red- range of cancer types has been associated with visual dis- ness. The anticonvulsant drug topiramate that is used to turbance (Al-Tweigeri et al. 1996; Gianni et al. 2006). One treat epilepsy can cause a syndrome consisting of acute study shows the prevalence of ocular toxicity from chemo- myopia associated with secondary angle-closure glaucoma, therapy to be 10.9% (Gianni et al. 2006). Fenretinide, a decreased visual acuity and ocular pain (Physicians’ Desk synthetic derivative of retinoic acid that has been studied Reference, 2005). This loss can be transient (reversible) or

permanent. The antiarrhythmic drug amiodarone can cause loneliness, cognitive impairment, depression and compro- visual disturbance, including blurred vision, coloured halos mised mobility. around lights, bright lights, glare and general decreased Hearing loss cannot be reversed because man lacks the vision (Johnson et al. 2004; US National Library of Med- ability to regenerate cochlear sensory cells. In spite of the icine and the National Institutes of Health, Medline Plus, progressive hearing loss that occurs during aging, it is 2005). Hydroxychloroquine, which has antimalarial actions noteworthy that only a minority of hearing-impaired and is also used to treat rheumatoid arthritis and lupus elderly utilize a hearing aid for amplification (Popelka erythematosis, can cause a vast number of ocular reactions, et al. 1998). Yet, use of a hearing aid to amplify sounds including blurred vision, halos around lights, photophobia, has been shown to improve functional status. One possible loss of foveal reflex, scotomas, retinal changes that can be reason for the low utilization of hearing aids among the irreversible, colour vision loss and decreased vision (Phy- elderly is that while amplification has considerable benefit sicians’ Desk Reference, 2005). Similar losses are caused in quiet listening situations, it is less beneficial in natural by the related drug chloroquine. Antipsychotic drugs of the environments with noisy backgrounds and multiple talkers. phenothiazine class, such as chlorpromazine, thioridazine, The simple whispered voice test (Eekhof et al. 1996) can fluphenazine, perphenazine and trifluoperazine, some of be used in the clinic or hospital room to determine whether which are used in the treatment of nausea and vomiting, a patient needs audiology testing. cause visual effects with prolonged usage, in part because Many factors contribute to hearing loss during aging. of the development of opacities in the anterior lens and They include noise exposure (typically prolonged occu- cornea (Pouget et al. 1976). Visual hallucinations have pational exposures), genetic predisposition, dietary factors, been associated with a broad range of drugs, including vascular disease, systemic disease, cancer, infections and atropine, dopamine agonists, antidepressants, anticonvul- inflammation, head injuries, ototoxic drugs and environ- sants, cardiovascular drugs and anti-inflammatory agents mental pollutants such as solvents and pesticides. Routine (Brown et al. 1980; Fisher, 1991; Holroyd, 1996; Faye, use of many medications (e.g. loop diuretics for hyper- 2000; Physicians’ Desk Reference, 2005). tension) can cause hearing loss.

Critical illness Hearing Cancer and its treatment can affect auditory perception. Changes in the auditory system with age Inner ear radiation for treatment of head-and-neck cancer Both physiological and perceptual changes in the auditory causes high-frequency hearing loss (‡2000 Hz) in a dose- system occur with advancing age (Gulya, 2000; Schiffman dependent fashion (Pan et al. 2005). Many cancer drugs et al. 2003). The pinna, or outer ear, which channels sound are ototoxic, including cisplatin (Boyer et al. 1990) and waves to the tympanic membrane (eardrum), demonstrates carboplatin (Takeno et al. 1994). Patients who after a several physiological changes, including loss of elasticity, stroke have left neglect (failure to recognize the left side of but these changes have little impact on auditory perception. the body in the absence of major visual problems) have The vibrations of the eardrum are transmitted to the three impaired ability on an auditory task that requires speeded bones of the middle ear (malleus, incus and stapes), which discrimination of sound elevation (Pavani et al. 2005). become more fixed with age and less effective in deform- Selective auditory deficits occur in patients with focal ing the oval window. Vibrations of the oval window set up right-hemispheric lesions (Clarke et al. 2002). High fever, similar vibrations in the internal fluid of the cochlea (the such as meningitis, can cause damage to the cochlea. Many snail-shaped structure in the inner ear) that cause mechan- medications that are used during a period of critical care ical waves to travel down the basilar membrane and bend can impair hearing (Shine & Coates, 2005). For example, the cilia of hair cells. Sensory presbycusis (hearing loss in the antibiotic gentamicin A causes hearing loss, and high the elderly) involves degeneration of hair cells and sup- doses of aspirin can cause tinnitus. Clonidine can cause porting cells of the cochlea, while neural presbycusis is a auditory hallucinations (Physicians’ Desk Reference, loss of cochlear neurons. Degenerative neural changes 2005). have also been reported in central auditory pathways, including the brain stem as well as the cortex. Hearing impairment in the elderly typically involves Taste mild-to-moderate high-frequency sensorineural hearing Changes in the taste system with age loss along with difficulty understanding conversational speech (Moscicki et al. 1985). The impairment in speech Perceptual losses in taste perception in the elderly have comprehension is because much of the energy of consonant been well documented, but the cause of these decrements sounds is concentrated in the higher frequencies. Differ- in the absence of medications and disease is not fully ence thresholds increase so that larger changes are needed understood (Schiffman, 1997; Schiffman & Zervakis, to detect a difference in the pitch of tones. The ability to 2002). The earliest studies that have quantified the number locate sound in space becomes more difficult. Overall, of taste buds and/or papillae (elevated lingual structures on hearing loss has many consequences beyond the ability to which taste buds are located) in older individuals using hear and understand speech, including inability to hear or large sample sizes have revealed substantial losses (Arey locate warning signals (emergency sirens, fire alarms, et al. 1935; Mochizuki, 1937, 1939; Moses et al. 1967). honking horns) as well as withdrawal and social isolation, Furthermore, later studies have found striking localized

deficits (i.e. regional losses) in taste perception on the anions, bitter compounds, sweeteners, acids, astringent tongues of elderly individuals (Bartoshuk et al. 1987; compounds, amino acids (including glutamate salts), fats Matsuda & Doty, 1995). The reports of perceptual loss of and polysaccharides and gums) is 4.7. The average loss in regional sensitivity are consistent with anatomical studies recognition, as measured by recognition threshold (elder- of the lingual surface that have found entirely flat areas on ly):recognition threshold (young), across this same quali- the surface of the tongue without papillae in old age tative range of compounds is also 4.7. The extent of loss (Kobayashi et al. 2001). However, there are other studies within a group (such as Na salts), however, is not uniform by established researchers using smaller numbers of but rather varies with the chemical structure of the com- elderly that suggest such losses of papillae and taste buds pounds. For both the young and the elderly thresholds for are minimal (Arvidson, 1979; Miller, 1986, 1988; Bradley, compounds with high energy or nutritional value such as 1988). When losses do occur, reduced renewal of the taste sugars, fats and amino acids are higher than thresholds for cells in the taste buds may be a factor. Taste cells normally many noxious bitter compounds that can be detected in replicate every 10–10.5 d, but delayed cell renewal has minute amounts. Losses in perception also occur at supra- been reported in taste buds of aged mice (Fukunaga, 2005). threshold concentrations. Suprathreshold tastants are per- Reduced levels of oestrogen and testosterone in the elderly ceived to be weaker by the elderly compared with the may contribute to the blunting of taste cell renewal since young (e.g. amino acids taste half as strong). There is lowering of these hormones is known to depress cell pro- reduced ability to discriminate between different supra- liferation in other tissues (Eartly et al. 1951; Hopper et al. threshold intensities of the same stimuli with age, with the 1972; Williamson, 1978; Zhang et al. 1998). Testosterone elderly needing a 2- to 3-fold greater concentration change has been shown to increase taste bud number in a rat to perceive a difference in intensity. The elderly also per- model (Cano et al. 1982). Some taste losses from normal ceive more off-tastes than younger subjects, which is fur- aging may occur at taste-cell membranes (e.g. altered ther exacerbated by medications and medical conditions. functioning of ion channels and receptors) rather than from The terms used to describe these taste losses are hypo- losses of taste buds or papillae. Alterations in neuro- geusia (reduction in taste intensity) and dysgeusia (distor- transmitter levels may also be involved. tion of taste). Taste signals from the taste buds are relayed to nucleus of the solitary tract (NST) in the medulla and then to the Medical conditions associated with taste complaints thalamus and cortical taste centres with ipsilateral projections from the taste buds to the thalamus. Signals from Taste changes have been reported in a vast range of medi- taste buds on the tongue and in the throat are transmitted to cal conditions (Schiffman, 1983a,b, 1997; Schiffman & the rostral portion of NST via the VIIth, IXth and Xth Zervakis, 2002). Examples of specific medical conditions cranial nerves. The caudal portion of the NST receives associated with taste alterations include: nervous system visceral sensory information originating in the oesophagus, disorders (Alzheimer’s disease, Bell’s palsy, damage to stomach, intestines and liver. The confluence of taste and chorda tympani, Guillain-Barre syndrome, familial dysau- digestive information in the NST explains why taste losses tonomia, head trauma, multiple sclerosis, Raeder’s para- can have an impact on a range of digestive processes; i.e. trigeminal syndrome, tumours and lesions); endocrine the NST is the first processing area in which taste signals disorders (adrenal cortical insufficiency, congenital adrenal can affect digestion by impacting on gastric secretion, hyperplasia, cretinism, Cushing’s syndrome, panhypopi- pancreatic exocrine secretion and secretion of insulin. tuitarism, hypothyroidism, diabetes mellitus, gonadal dys- Imaging studies suggest some taste loss with age may be a genesis, pseudohypoparathyroidism); nutritional disorders result of shrinkage of taste projection areas in the upper (niacin and Zn deficiency); amyloidosis and sarcoidosis; part of the medulla oblongata in the brainstem (Yamamoto cancer; chronic renal failure; cystic fibrosis; facial hypo- et al. 2005). Inflammatory processes that occur in many plasia; glossitis and other oral disorders; hypertension; medical conditions can potentially induce neural damage influenza-like infections; laryngectomy; leprosy; liver dis- and apoptosis along taste pathways and may account for ease including cirrhosis; major depressive disorder; oral some complaints of reduced taste sensitivity in the elderly. Crohn’s disease; radiation therapy; Sjo¨gren’s syndrome; Environmental pollutants also contribute to some taste thermal burn. In most of the studies that have reported losses (see Schiffman & Nagle, 1992). gustatory alterations in specific medical conditions medi- Perceptual changes in taste with aging are more fully cation usage was not controlled, so it is impossible to documented than physiological changes (Schiffman, 1993; determine the relative contribution of disease status and Schiffman & Zervakis, 2002; Schiffman et al. 2003, 2007). medications to taste changes. Detection and recognition thresholds for tastes are moder- ately elevated in older individuals compared with a Medications implicated in taste complaints younger cohort; i.e. more molecules (or ions) are needed by the elderly to perceive or recognize a tastant compared Community-dwelling elderly individuals aged >65 years with younger individuals. Taste losses occur for individual who are not critically ill consume an average of 2.9–3.7 compounds (e.g. NaCl) in simple aqueous solutions as well medications daily (Lewis et al. 1993), and this number as in mixtures in which other ingredients mask important increases substantially for critically-ill elderly patients in food components. The average loss, as measured by hospitals and nursing homes. Hundreds of medications, detection threshold (elderly):detection threshold (young), including all major drug classes, have been associated for a range of compounds (including Na salts with different clinically with taste complaints such as ‘loss of taste’,

‘altered taste’ and ‘metallic taste’ (Schiffman & Zervakis, drugs as well as their metabolites can accumulate in taste 2002; Schiffman et al. 2003). These medications include: buds over time to reach concentrations that are greater than AIDS- and HIV-related therapeutic drugs; amebicides; taste detection thresholds. anthelmintics; anticholesteraemics and antilipidaemics; Transient complaints of dysgeusia (e.g. metallic taste) anticoagulants; antihistamines; antimicrobial agents; anti- sometimes occur on injection of drugs at concentrations proliferative and immunosuppressive agents; antirheumatic, below the taste threshold, and this treatment can be antiarthritic, analgaesic, antipyretic and anti-inflammatory accompanied by emesis. The cause of dysgeusia in this agents; antiseptics; antispasmodics; antithyroid agents; case is likely to be a result of activation (by injection) of antiulcerative drugs; antivirals; agents for dental hygiene; pressure receptors in the arterial system that are innervated bronchodilators and antiasthmatic drugs; cardiovascular by the IXth cranial nerve and that project to the NST, medications including diuretics, antiarrhythmic, anti- which also receives taste input. hypertensive and antifibrillatory agents; hyper- and hypo- glycaemic drugs; hypnotics and sedatives; muscle relaxants Critical illness and drugs for the treatment of Parkinson’s disease; psycho- pharmacological drugs including antiepileptic drugs; sym- Taste changes have been reported in many critical ill- pathomimetic drugs; vasodilators (Schiffman, 1983a,b, nesses, and clinical studies of patients with wasting indi- 1997; Schiffman et al. 2003). cate that these losses are especially severe (Schiffman & The actual prevalence of medication-induced losses is Wedral, 1996). For cancer, taste alterations occur in not yet known because quantitative studies of taste per- untreated patients (Brewin, 1980; Ovesen et al. 1991) as ception in large populations taking specific medications well as in those undergoing chemotherapy (Nielsen et al. have not yet been performed. Thus, it is not yet clear 1980; Fetting et al. 1985) and radiation (Conger, 1973). An whether adverse taste complaints reported clinically are overview of studies suggests that cancer and its treatment indeed gustatory (or olfactory) or whether they are actually impair the ability to detect the presence of the taste of caused in part by the medical conditions they are designed sweet, sour, salty and bitter taste qualities; in addition, to treat. Furthermore, little is known about the sites of there is reduced ability to perceive suprathreshold con- action or cascade of cellular events by which medications centrations of tastants and thus to discriminate and identify induce taste complaints. However, medications can poten- tastes (Schiffman & Graham, 2000). Distortions of taste tially impact on taste perception at several levels of the (i.e. dysgeusia) also commonly occur. DeWys & Walters nervous system, including the peripheral receptors, che- (1975) have suggested that ‡ 50% of patients with cancer mosensory neural pathways and/or the brainstem and brain. have impaired taste functioning at some point during the At the peripheral receptors drugs can induce a taste of their course of their disease and treatment. The duration of own or modify transduction mechanisms (e.g. intracellular losses can last from several weeks to 6 months, or longer messengers of the adenylate cyclase system) in taste (Conger, 1973; Mossman & Henkin, 1978; Ophir et al. receptor cells. Drugs can also alter activity along the gus- 1988; Maes et al. 2002; Schiffman et al. 2007). Altered tatory pathways when they permeate into the brainstem or taste perception in cancer can be caused by metabolic brain itself. Some areas of the NST have complexes of changes induced by the presence of a neoplasm as well as microvessels that are permeable to blood-borne compounds damage to the sensory receptors by radiotherapy and che- (Gross et al. 1990), and both extracellular and intracellular motherapy. Oral infections (fungal, viral, bacterial), ulcers, pathways are known to exist that circumvent the blood– drug-induced stomatitis and dry mouth can also play a role brain fluid barrier (Broadwell & Sofroniew, 1993; Broad- in taste complaints. Some of the many chemotherapeutic well et al. 1996). Some drugs interfere with cell turnover drugs associated with altered taste perception include of taste receptors (e.g. by blocking mitosis); examples cisplatin, carboplatin, cyclophosphamide, doxorubicin, include chemotherapeutic agents and some antibiotics. 5-fluorouracil, levamisole and methotrexate (Epstein et al. When the taste of the medication itself is the cause of 2002; Schiffman & Zervakis, 2002). It is probable that the complaint, the drug may reach the receptors in three chemotherapeutic medications that target rapidly-dividing different ways: oral ingestion of the dosage; excretion into cancer cells also impact on the turnover and replication of the saliva; diffusion from lingual blood vessels to activate taste cells. Alterations in taste acuity can also occur after receptors on the basolateral and even apical side of taste allogeneic bone-marrow transplantation (Mattsson et al. cells via permeation (termed intravascular ‘taste’; see 1992; Epstein et al. 2002). It should be noted that some of Holland et al. 1991). An example of a drug that can induce the taste complaints in cancer are not a result of altered unpleasant tastes by salivary excretion as well as by perception per se but are due to learned aversions that arise intravascular taste is the protease inhibitor saquinavir. during the noxious effects of radiotherapy and chemo- After a 600 mg dose the concentrations of saquinavir in therapy (Schiffman & Graham, 2000). Patients associate saliva and in plasma are approximately 0.0127 mM and the taste of foods and beverages consumed shortly before 0.22 mM respectively (Hoetelmans et al. 1997). Both these or after treatment with the negative side-effects of radio- salivary and plasma levels of saquinavir exceed the taste therapy and chemotherapy. detection thresholds of saquinavir of 0.0029 mM in un- Taste disorders frequently occur after a stroke, with infected patients and 0.0061 mM in unmedicated patients hypogeusia being the most-frequent gustatory symptom with HIV (Schiffman et al. 1999). For most drugs, how- (Heckmann et al. 2005). However, left posterior insular ever, the salivary or plasma levels tend to be lower than the stroke can lead to increased taste sensitivity contralateral to taste threshold values (see Schiffman et al. 2002). Yet, the lesion (Mak et al. 2005). Taste disorders also occur in

end-stage liver disease (Bloomfeld et al. 1999). Malnutri- 2050 is ‡ 230 million. Loss of the ability to identify tion in the critically-ill patient, independent of the specific odours for most individuals tends to occur gradually over type of medical condition, can clearly affect the turnover/ the years, and some elderly individuals are not aware of reproduction of taste cells and reduce their numbers the problem until it becomes very troubling. Older indivi- (Schiffman, 1983a,b, 1997). Furthermore, the burden of duals also lose the ability to make discriminations among taste disorders from medications is elevated in a critically- different odours. It is estimated that young adults with a ill geriatric population because of the extensive use of normal sense of smell can distinguish £10 000 different prescription drugs. It will be shown (see pp. 339–341) that chemicals, although there appear to be some genetic dif- hypogeusia and dysgeusia are more prevalent in one group ferences among individuals in the qualitative range of critically-ill patients than in non-medicated or even (Menashe et al. 2003). The number of compounds that can medicated community-living controls. be differentiated is greatly reduced in the elderly, who first lose the ability to make fine discriminations between odours with similar qualities (e.g. different types of cof- Smell fees) and ultimately, in more extensive loss, between odours with different qualities (e.g. beef v. lemon). Changes in the olfactory system with age Odour sensations are initiated when odorants bind to Medical conditions and environmental exposures olfactory receptors on the cilia of olfactory receptor neurons (ORN) situated in the olfactory epithelium high within Smell losses that occur from normal aging are compounded the nasal vault (Schiffman, 1997; Schiffman & Zervakis, by a wide range of medical conditions (e.g. endocrine, 2002). There are extensive anatomical and physiological neurological, nutritional, psychiatric) as well as environ- changes in the olfactory epithelium with age, including an mental exposures. Numerous medications such as anti- increase in ORN apoptosis (programmed cell death), anginal drugs (diltiazem, nifedipine), antimicrobial agents decreases in the rate of basal cell proliferation, decreased (allicin, streptomycin) and antithyroid agents (carbimazole, thickness of the olfactory epithelium, decreased number of methimazole, methylthiouracil, propylthiouracil), as well cilia and supporting microvilli and increased accumulation as radiation therapy and chemotherapy, have been reported of electron-dense granules in supporting cells (Schiffman, to affect the sense of smell (Schiffman, 1983a,b, 1997; 2000). Over time, the olfactory epithelium is gradually Schiffman & Zervakis, 2002; Schiffman et al. 2003). replaced by non-olfactory (i.e. respiratory) epithelium with Conductive losses in which there is obstruction of nasal a subsequent loss in the receptor area. The axons of the airflow to the olfactory epithelium, e.g. sinusitis, polyps, bipolar ORN pass through small openings in a bone known tumours, adenoid hypertophy and allergic rhinitis lead to as the cribriform plate where they synapse in neural masses hyposmia and/or anosmia. Sensory and/or neural losses termed glomeruli in the olfactory bulb. During the aging (e.g. from upper respiratory infections, head trauma and process the olfactory bulb takes on a ‘moth-eaten’ inhaled environmental toxins) often result from damage to appearance as glomeruli atrophy and fibres degenerate and the ORN, the olfactory bulb and/or central projection disappear. Central olfactory projection areas are especially areas. ORN are especially vulnerable because they are vulnerable to aging, with many anatomical and physiolo- exposed to the external environment and thus can be gical changes in the hippocampus, amygdaloid complex directly impacted on by inhaled environmental agents, and hypothalamus, which include reductions in cell num- including viruses. Damage to the olfactory bulb (and even ber, damage to cells and diminished levels of neuro- higher cortical areas) can also occur because ORN serve as transmitters. a direct conduit for the transport of substances from the An overview of odour threshold studies (Schiffman et al. nasal cavity to the brain. When ORN are damaged by 1976) indicates that detection and recognition thresholds injury (e.g. infectious agents and toxins in inhaled air) the for a broad range of individual volatile compounds (as well regenerating olfactory axons are generally unable to tra- as odour mixtures) are elevated for elderly individuals verse the holes in the cribriform plate to reach the olfactory compared with their younger counterparts. This loss in bulb. This breakdown in appropriate connections of olfactory sensitivity at the threshold level typically begins regenerating neurons can create aberrant synaptic associ- in the 6th decade of life, with progressively greater losses ations that lead to dysosmia (distortion of smell). Ineffec- into the 7th and 8th decades. Impairment of odour per- tual regeneration (e.g. after a virus) can also result in the ception at suprathreshold levels in the elderly is generally replacement of olfactory epithelium by respiratory epithe- more pronounced than that for taste. The prevalence of lium, scarring of the olfactory epithelium, resulting in impaired ability to identify odours increases from 17.3% gradual reduction in olfactory receptor area. for individuals aged 60–69 years, to 29.2% for individuals Olfactory losses are especially profound in certain dis- aged 70–79 years and 62.5% for the 80–97-year-olds ease states such as Alzheimer’s disease and Parkinson’s according to a population-based cross-sectional study in disease that are prevalent in an older population the USA (Murphy et al. 2002). This impairment or (Schiffman et al. 1990, 2002; Schiffman & Zervakis, diminished sensitivity of smell is termed hyposmia. Total 2002). Meta-analyses of olfactory studies of patients with absence of smell is termed anosmia. Given these US pre- Alzheimer’s disease indicate that severe losses can occur valence data along with UN projections of global popu- in five olfactory domains: threshold detection; recognition; lation growth (United Nations, 1997), the number of discrimination; identification; olfactory memory. With the individuals projected to have olfactory loss worldwide by possible exception of losses in sensitivity at the threshold

level, all these olfactory domains are impaired relative to disease exacerbate age-related somatosensory impairments age-matched controls in the earliest stages of Alzheimer’s (Schiffman et al. 2003). Many drugs and medical treat- disease. Neural degeneration along olfactory pathways ments have somatosensory side effects, including HIV (e.g. olfactory bulb, anterior olfactory nucleus, olfactory drugs (zalcitabine, stavudine), statins and chemotherapy. tubercle, amygdala, prepiriform cortex, hippocampus) is Examples of somatosensory symptoms attributed clini- also more pronounced in Alzheimer’s disease compared cally to numerous medications include numbness and with age-matched controls. tingling.

Critical illness Critical illness Loss of smell occurs during the course of cancer and its Patients with unilateral oral or pharyngeal cancer who are treatment (Lehrer et al. 1985; Schiffman & Graham, 2000). treated with bilateral radiotherapy (to reduce the potential Olfactory function in patients with nasopharyngeal carci- for metastases) have deterioration of intra-oral sensation noma deteriorates after radiotherapy (Ho et al. 2002), and even on the non-tumour side 6 months after treatment, and anticancer drugs such as tegafur cause olfactory dysfunc- there is no recovery 1 year after radiotherapy (Bodin et al. tion (Nakamura et al. 1995). As with taste, left posterior 2004). The antineoplastic agent cisplatin causes sensory insular stroke can lead to increased sensitivity to smell neuropathies in a dose-dependent fashion (Krarup-Hansen contralateral to the lesion (Mak et al. 2005), and olfactory et al. 1993). Somatosensory deficits following stroke are disorders occur in end-stage liver disease (Bloomfeld et al. common (Kim & Choi-Kwon, 1996); examples of losses 1999). Furthermore, the sense of smell is severely impaired include impaired fingertip texture discrimination and wrist in chronic renal failure (Griep et al. 1997). position sense (Carey et al. 2002) and referred sensations such as misplaced localization of touch (Turton & Butler, 2001). Upper-extremity neuropathies (Honet et al. 1976; Somatosensory system Seyfer et al. 1985) have been reported after cardiac sur- Changes in the somatosensory system with age gery, including sensory neuropathies involving the ulnar nerve. The somatosensory system comprises a variety of receptors in the skin that transmit sensations of touch, temperature, pressure and pain. Skin receptors can be divided into two Effect of history of critical care on sensory performance principal types: free nerve endings; encapsulated nerve (all five senses) in patients with cardiovascular endings, such as Meissner corpuscles, Pacinian corpuscles conditions: review of study and Merkel discs. Studies of elderly individuals (Bolton et al. 1965; Cauna, 1965) indicate that there are reduced It has long been known that unusual sensory complaints numbers of various touch receptors in the skin with age; are reported clinically after cardiac surgery (Ellis, 1972). Meissner and Pacinian corpuscles have the greatest loss, Remarkably, however, neither the extent nor type of loss both in numbers and morphology, and free nerve endings has yet been quantified across all five senses concomitantly have the least loss. The physiological loss of Meissner’s in individuals with a history of cardiovascular surgery. The corpuscles is correlated with the perceptual loss of skin purpose in performing the research that will be reviewed sensitivity with aging (Kenshalo, 1986). briefly was to evaluate and compare sensory performance Perceptual decreases in touch sensitivity with age have (all five senses as well as cognition) in three groups of been reported using a variety of tasks for measuring touch subjects: (1) patients who had undergone coronary artery perception, including the two-point discrimination task, bypass surgery (n 38); (2) patients with cardiovascular orientation of line grating, point localization, detection of a conditions but with no history of surgery (n 125); (3) gap in a disc, line length discrimination and line or point healthy non-medicated age-matched controls (n 65). The orientation (Schiffman et al. 2003). Although these tests of study design allowed the determination of whether the touch quantify different facets of touch perception and combined impact of cardiovascular surgery plus cardio- have different thresholds, the loss appears to be generic vascular drugs on sensory performance was greater than because scores decline at about the same rate (1%/year) the impact of the use of cardiovascular drugs alone. The with age. Acuity declines faster at the fingertip than at the three groups tested were statistically equivalent in age forearm or lip (Stevens & Patterson, 1995). Thermal sen- (mean 73 (range 65–84) years) and duration of education sitivity also deteriorates with age, with the greatest re- (16 (range 12–21) years). The mean number of prescription duction at the extremities such as the fingers, toes and sole medications taken by patients who had undergone coronary of the foot (Stevens & Choo, 1998). Vibratory sensitivity artery bypass surgery was 4.5; for the patients with cardio- also declines with age, with preferential loss at higher vascular conditions but with no history of surgery the mean frequencies (Verrillo, 1980). number was 3.6. The healthy non-medicated age-matched controls took no medications other than over-the-counter vitamins. The exclusion criteria for all groups included: Diseases and medications poor general health at the time of testing; current use of Peripheral neuropathies (attributed to diabetes, thyroid antibiotics; known problems with sensory functioning disorders, rheumatoid arthritis, HIV infection, alcoholism (e.g. AMD, glaucoma, hearing aids in both ears, chemo- and vitamin B12 deficiency) as well as peripheral vascular sensory disorders unassociated with medications); current

Table 1. Mean scores and intra-individual variability over three sessions on tests of the ﬁve senses and cognition for three groups of subjects Group...... Coronary Cardiovascular medication Non-medicated https://www.cambridge.org/core bypass surgery (no history of surgery) Mean Mean Mean Mean intra-individual Mean intra-individual Mean intra-individual Test type and description of method score variability (%) score variability (%) score variability (%)

Taste thresholds . https://doi.org/10.1017/S0029665107005599 NaCl DT (mM) 18.663.37.39 44.45.03 45.7 DT were determined by an ascending forced-choice method (see Schiffman et al. 2002) using fourteen successive dilutions of NaCl that differed by 0.25 log units with a . IPaddress: maximum concentration of 0.56 M. The DT was defined as the lowest of five consecutively correct selections of increasing concentration at which the subject correctly distinguished the NaCl solution as stronger than a water control NaCl RT (mM) 39.841.118.732.017.429.6 170.106.203.244 Using the paradigm for DT described earlier, the subject was also asked to identify the stronger taste of a pair (tastant and water control) as salty, sweet, bitter, sour, metallic, chalky or other. The RT was defined as the lowest concentration at or above the DT at which the subject could correctly identify the taste of the NaCl solution as , on salty 339 gut the and illness Eating, ......

04 Oct2021 at04:38:03 Sucrose DT (mM) 25 5327153284114299 Method same as for NaCl DT. Fourteen successive dilutions were prepared that differed by 0.25 log units using a maximum concentration of 0.56 m for sucrose Sucrose RT (mM) 40.728.925.919.125.319.8 The RT was deﬁned as the lowest concentration at or above the sucrose DT at which the subject could correctly identify the taste as sweet Quinine hydrochloride DT (mM)18.845.08.31 42.06.49 38.3

, subjectto theCambridgeCore termsofuse,available at Method same as for NaCl DT. Fourteen successive dilutions were prepared that differed by 0.25 log units using a maximum concentration of 0.68 mM for quinine hydrochloride Quinine hydrochloride RT (mM)29.438.718.534.818.529.5 The RT was defined as the lowest concentration at or above the DT at which the subject could correctly identify the taste as bitter Smell tests Butanol DT (ml/l water) 0.0476 57.40.0269 48.50.0059 55.5 Butanol DT were determined using a two-alternative ascending forced-choice procedure (Schiffman et al. 2002). The test set consisted of thirteen concentrations of 1-butanol in deionized water separated by threefold dilution steps (the highest concentration was 40 ml/l water). The DT was defined as the lowest of five correct consecutive choices of five increasing concentrations Smell identification 5.30 46.96.19 36.85.91 37.4 Subjects were presented with a list of twenty-seven names of odorous substances. Twelve of the names were target substances presented to subjects in amber bottles while the other fifteen names served as ‘distracters’. The target odours included: almond, ammonia, baby oil, cinnamon, coffee, garlic, lavender, orange, peppermint, tobacco, vanilla and vinegar. Subjects were instructed to sniff the odour from the bottle, and to place the bottle number next to one of twenty-seven odour descriptors. The test score was the total number correct of twelve target substances Vision tests Near vision: Right eye 36.940.633.139.525.433.6 https://www.cambridge.org/core/terms Downloaded from

Table 1. Continued Schiffman S. S. 340

https://www.cambridge.org/core Group...... Coronary Cardiovascular medication Non-medicated bypass surgery (no history of surgery) Mean Mean Mean Mean intra-individual Mean intra-individual Mean intra-individual Test type and description of method score variability (%) score variability (%) score variability (%) . https://doi.org/10.1017/S0029665107005599 Near-visual acuity was assessed using a Rosenbaum Pocket Vision Screening Chart (Western Ophthalmics Corporation, Lynnwood, WA, USA). Each eye was tested separately with the subject wearing his or her personal visual correction when . IPaddress: needed and the non-tested eye occluded. The chart was presented at 0.35 m (a typical reading distance) with good overhead illumination. The near-visual acuity score was determined to be the lowest line at which a subject could correctly identify at least half the numbers or symbols. Mean score is the denominator of 170.106.203.244 the distance equivalent, e.g. 20/20, 20/30, i.e. 20/36.9 is worse than 20/33.1 Near vision: Left eye 37.446.536.841.735.435.5 As right eye Hearing tests , on Hearing: Right ear (decibels) 36.912.936.510.935.812.3

04 Oct2021 at04:38:03 Thresholds (decibels) for six pure tones (500, 1000, 2000, 4000, 6000, and 8000 Hz) were determined with a staircase method (for description of staircase procedure, see Weiffenbach et al. 1982) using the Maico 25 portable air conduction audiometer and an audiocup headset (Eden Prairie, MN, USA). A total score was computed by adding the decibels required to reach threshold at each of the six pure tones and dividing by six. Lower total scores indicated better performance Hearing: Left ear 38.015.537.512.036.814.9 , subjectto theCambridgeCore termsofuse,available at Same as right ear Touch test Touch test (mm) 2.61 40.92.37 36.72.30 29.6 Tactile spatial sensitivity thresholds (i.e. cutaneous spatial resolution) were measured by assessing orientation of spatial gratings (JVP Domes, Stoelting Company, Wood Dale, IL, USA; Van Boven & Johnson, 1994; Stevens & Choo, 1998). Eleven probes were employed with different equidistant bar–groove widths that ranged from 0.35 mm to 4 mm. The experimenter pressed a probe on the finger pad with the gratings in either the vertical (along the finger) or the horizontal (across the finger pad) orientation. The staircase method was used to determine thresholds for tactile sensitivity utilizing a ‘one incorrect up, two correct down’ rule. This paradigm continued until six reversals (changes in direction) were recorded, with the average of the track changes being the threshold. The score is the mean spatial resolution (mm) Cognitive tests Immediate word-pair recall 7.73 49.17.76 43.07.71 45.3 Subjects read aloud a list of thirteen word pairs, with each pair presented at 3 s intervals. After a second presentation of these same word pairs subjects were given the cue words (first words of each pair) on a page, but the target words (second words of each pair) were absent (blank line). Subjects were asked to write on the blank lines as many of the pair-associated words as they could remember. The maximum score attainable score was thirteen correct Delayed word-pair recall 6.50 50.76.64 51.16.49 51.5 Eating, illness and the gut 341

dental problems; current cancer; peripheral neuropathy; a score <25 on the mini mental status examination (Folstein 8 5 . . et al. 1975), which assesses cognitive functioning. Subjects in the coronary artery bypass surgery group were tested between 3 and 6 months post surgery to ensure adequate enrolment of patients who met both the inclusion and exclusion criteria. All subjects were tested in triplicate over 015 07 49 . . a 2-month period, with each evaluation separated by approximately 1 month. Multiple testing was performed to investigate and compare short-term intra-individual fluc- tuation or lability of the five senses and cognition, with repeated testing over a short time period when little change 545 35 . . in perception was expected. The scores on the sensory and cognitive tests along with brief descriptions of the test protocols are given in Table 1. Analysis of the scores reveals several major findings. First, the greatest losses for the patients who had undergone coronary bypass (who were prescreened to eliminate those 116 11 41 . . with serious cognitive dysfunctioning) are for taste and smell thresholds. Taste thresholds for this group of patients range from 1.6to2.5 times higher than thresholds for the patients who were taking cardiovascular drugs but had no history of surgery. Taste thresholds for the patients who 841 15 . . had undergone coronary bypass range from 1.6to3.7 times higher than thresholds for non-medicated subjects. Smell thresholds for the bypass patients are 8.1 times higher than thresholds for non-medicated subjects and 1.8 times higher than those for patients taking cardiovascular drugs without a history of surgery. Patients taking Ca-channel blockers 228 10 62 . .

5 tend to have the greatest losses. Furthermore, elderly patients who had undergone coronary artery bypass surgery reported more off-tastes for each of the taste stimuli tested (e.g. bitter in addition to sweet for sucrose and metallic in addition to salty for NaCl). Taking all tests together, the numerical value of the mean scores for the patients who had undergone coronary artery bypass surgery on sixteen or seventeen tests in Table 1 are in the direction of poorer performance compared with scores for patients with cardiovascular conditions without a history of surgery or the healthy non-medicated controls (P<0.000015). Further- more, the intra-individual variability is also numerically greater for all tests for the patients who had undergone coronary artery bypass surgery (P<0.0000008). The probable cause of numerically-lower scores and greater variability in the elderly patients who had undergone coronary artery bypass surgery is likely to be multifactorial, involving the consequences of surgery (e.g. type and duration of anaesthesia, polypharmacy in conjunction with anaesthesia, invasiveness of the surgery, microemboli, post- operative hyperthermia and periods with reduced cerebral perfusion), other medical conditions and current medications. Statistical analysis reveals that the reduced performance on sensory tests is only weakly correlated or not

. (2002). The four odorants of moderate intensity were: geraniol correlated with cognitive performance. This result is probably, in part, because none of the subjects in the study et al were demented; all participants had been prescreened on the mini mental status examination to ensure their intel- lectual competence in order to eliminate potential subjects presented with a pagepairs containing and each an of adjacent thewords blank cue as line words they and (first could asked words)the remember to of thirteen without recall the pairs. the as thirteen The opportunity many maximum of of score being the attainable able pair-associated score to was re-read thirteen correct were presented with asymbol. key The that subject pairs was eachthat then digit correspond instructed from to to 1 the fill toallotted symbols in 9 90 presented s rows with to directly of a write above blank specific theskipping the digits boxes geometric any boxes. in with items as Subjects the many were digits possible consecutive boxes in a row without Schiffman (floral), methyl salicylate (minty), benzaldehydeinstructed (almond) to and sniff butanol. one SubjectsSubjects bottle were then containing counted the backward targetexaminer. by odour intervals Subjects and of were then 3 sequentially trywere for presented to 7 asked with remember s to a from it. identify set aremember. which number of Each of given the odour the by four was four the odorants,was presented had and based twice, the on for odour the a thatmaximum total total they score number of were of eight asked correctly-remembered trials, to smells, and with scoring eight as the with cognitive impairments triggered by coronary artery After a 5–10 min delay following the task described earlier, subjects were again The symbol digit modalities test evaluates processing speed (Smith, 1982). Subjects Smell memory was assessed for four odorants using procedures described by bypass surgery (see Russell & Bornstein, 2005). Thus, Symbol digit modality 37 Smell memory

DT, detection threshold; RT, recognition threshold. while sensory losses are not necessarily a consequence of

cognitive loss, sensory and cognitive losses in elderly Acknowledgements patients who have undergone coronary artery bypass sur- Research described in this paper was supported in part by gery may be a result of a common cause or unrelated NIH AG00443. causes. Furthermore, the absence of significant differences between the mean values for the three repetitions of the tests in patients who had undergone coronary artery bypass surgery suggests that mean sensory and References cognitive performance for the group was stable from Al-Tweigeri T, Magliocco AM & DeCoteau JF (1999) Cortical 3 months to 6 months in spite of substantial intra- blindness as a manifestation of hypomagnesemia secondary to individual variation. cisplatin therapy: case report and review of literature. Gyne- cologic Oncology 72, 120–122. Al-Tweigeri T, Nabholtz JM & Mackey JR (1996) Ocular toxicity and cancer chemotherapy. A review. Cancer 78, 1359– Consequences of sensory losses for nutrition 1373. 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